ABSTRACT The primary goal of the active R01 grant is to examine the long-term impact of marijuana use on cognitive function and health outcomes in persons living with HIV (PLWH). This is being accomplished by building a longitudinal cohort of approximately 480 PLWH from three different locations in Florida (Gainesville, Tampa, Miami) and assessing marijuana use, cognitive function, and health outcomes annually for 4 years. The supplement is within the scope of the active R01 project and extends the parent study by including a subsample of participants relevant to Alzheimer's disease and its related dementia (ADRD), specifically, those who showed evidence of amnestic mild cognitive impairment (MCI). Specifically, we will add an additional screening criterion to identify at least 25 persons who are otherwise eligible, but are aged 60+ years and have a positive screening test for MCI at the time of enrollment, as well as 25 age-matched controls who do not screen positive for MCI. These participants will be recruited at the University of Florida (Gainesville) and the Florida International University (Miami) sites. They have additional cognitive and functional assessments to help determine whether they meet criteria for MCI, and to help differentiate between different types of cognitive impairment (e.g. HIV-associated neuropathy, acute marijuana intoxication, or ADRD). We will also obtain stool and saliva samples for shotgun whole-genome sequencing to characterize the gut and oral microbiome (which will be done by the University of Louisville team). By leveraging the ongoing cohort, specific aims of this supplement include examining: the association between marijuana use and microbiome (Aim 1), the association between microbiome and MCI (Aim 2), and mediating role of microbiome between marijuana use and MCI (Aim 3). The study will give us preliminary data to disentangle the complex relationships among marijuana use, microbiome, and MCI in the context of HIV. We will also initiate an ADRD working group as part of the parent grant, to monitor the procedures and plan for future research based on the pilot findings.